Introduction: Several evidences suggest the potentiality of the glucosylxanthone mangiferin (MG) to modulate some of the molecular targets implicated in neuropathic pain mechanisms, especially central sensitization, through of its long term effects mediated by transcriptional changes. Nevertheless, a transient mechanism of MG on nociceptive pathway could be implicated. Previously, we advised that MG could be used to treat neuropathic pain supported in preclinical data and preliminary clinical reports with Mangiferaindica L. extract formulations that contain 15–20% of this polyphenol. Material and Methods: The present study examines its possible effect on pain-related behaviors in a tonic acute pain model (formalin test at 5%) and in a chronic constriction injury (CCI) model to clarify the underlying transient and long-term mechanisms. Results: Acute administration of MG (10–100 mg/kg, i.p.) reduced licking/biting exclusivity in the tonic phase of formalin test in a naloxone and yohimbine-sensitive manner. This effect was enhanced by a nonselective nitric oxide synthase (NOS) inhibitor (NG-monomethyl-L-arginine) and by a non-competitive N-methyl-D-aspartate (NMDA) antagonist (ketamine), but it was reversed by the NOS substrate (L-arginine). Pre-treatment with intrathecal yohimbine prevented the anti-hypernociceptive effect of systemic MG. Pre-treatment during 4 days before surgical and 3 days after CCI with MG (50 mg/kg, i.p.) reduced mechanical hypernociception and decreased the signs of Wallerian degeneration (WD) of the sciatic nerve. MG improved the PC-12 cellular viability exposure to glutamate-mediated neuronal death, also involved in neuropathic pain. Conclusions: The findings of this study suggest that MG shows ability to decrease tonic pain in the formalin test. A transient activity of this xanthone on nociceptive pathways mediated by α2 adrenergic receptors in cooperation with the opioid system could be involved, at least in part, in this effect. Its neuroprotective effect by preventing WD in mononeuropathic rats could be implicated in the mechano-antihypernociceptive long-term mechanisms. Financial Support: Projects MINSAP № 0808001 (Cuba), CAPES № 120/2011 (Brazil), and FONDECYT № 1130601 (Chile).